Increased IgG and oligoclonal bands (OGBs) in the CSF and brains of patients with chronic inflammatory or demyelinating CNS disease provide clues to the nature of disease. OGBs appear almost exclusively in chronic infectious diseases of the CNS, and are antibody directed against the disease-causing organism, thus providing a rationale for our hypothesis that in chronic CNS inflammatory or demyelinating diseases of unknown cause, the OGBs target the antigens that trigger disease. We have analyzed the sequences of intrathecally synthesized IgG in subacute sclerosing panencephalitis (SSPE), a fatal chronic measles virus infection of the brain, and demonstrated features of antigen-driven selection. We produced recombinant IgG from these sequences, selected disease-relevant recombinant IgG from phage-displayed Fab libraries, and demonstrated their reactivities to the causative measles virus. We will use SSPE as an experimental paradigm to develop strategies and techniques to identify disease-relevant IgG and their corresponding antigens in inflammatory or demyelinating CNS disease of unknown cause. We will synthesize recombinant IgG from candidate SSPE brain-derived sequences and identify disease-relevant antibody by direct analysis in immunostaining or ELISA with SSPE brain, or display them on phage surfaces to select the appropriate IgG by biopanning on SSPE brain. We will also identify the IgG sequences expressed by individual resident B cells in SSPE brain by single-cell PCR. Finally, we will develop strategies to detect very rare antigens in situ by immunoblotting, immunoprecipitation, or by selection from phage-displayed antigen and peptide libraries. We are uniquely prepared to carry out these studies because we have pathologically-verified SSPE brains, and have already demonstrated an expertise to use disease-relevant recombinant IgG to identify their targets. This paradigm will provide a careful and methodological approach to elucidate the humoral immune response in the human CNS. It will also allow the creation of exquisitely sensitive immunologic techniques to identify disease-relevant IgG and their disease-triggering antigens in other inflammatory or demyelinating CNS diseases of unknown cause, including multiple sclerosis, acute disseminated encephalomyelitis, sarcoidosis, and the CNS vasculitides. Determining the cause of these devastating neurologic diseases will have profound implications not only for early diagnosis but also for prevention of disease.